Researchers Present Findings at 2016 TRIO Combined Sections Meeting

by Thomas R. Collins • April 11, 2016

Investigators from around the country and Canada presented their findings at the Triological Society Combined Sections Meeting, held in January in Miami Beach, Fla. Here are some research highlights from the event.

Researchers using DNA analysis and a sophisticated analysis of published literature have found four “master regulators” in charge of four molecular networks that appear to be involved in the development of keloid tumors, offering up future areas of focus for the development of therapies for these hard-to-eliminate lesions.

Keloids are benign fibroproliferative tumors more commonly found in people with darker skin, including African-Americans and Asians. They have an incidence rate of 4% to 16%. One of the most troublesome aspects of keloids is that they recur so frequently after treatment, said Laura Garcia-Rodriguez, MD, a fourth-year resident at Henry Ford Health System in Detroit. “Not only are they aesthetically displeasing, [but] they can cause pain, pruritis, and loss of function,” she said. “The problem with keloids is that there can be up to a 50% recurrence rate. It’s something very hard to explain to a patient who has a very large keloid on [his or her] face.”

Researchers extracted DNA from six keloid tissue samples and six normal tissue samples, then performed genome-wide profiling, finding 152 genes that were differentially methylated between the keloid tissue and the normal tissue.

The 10 with the highest statistical significance were analyzed using causal network analysis (CNA) to find networks with directionality that connect upstream regulators with downstream expression products. The CNA is part of the Ingenuity Pathway Analysis software that includes a database of about five million observations from published literature.

The researchers identified four master regulators and 19 intermediate regulators. A master regulator is a gene or drug positioned as the central or master hub that has the ability to command or influence downstream events, Dr. Garcia-Rodriguez said. She likened master regulators to the conductors of an orchestra and intermediate regulators to individual instruments in an orchestra. The master regulators identified (the chemical drugs tributyrin and pyroxamide, which the analysis showed are likely activated in the relevant networks, and the molecules PRKG2 and PENK, which were predicted to be inactivated) all appear to relate back to tumor protein 53 (TP53), a tumor suppressor.

Inactivation of the p53 tumor suppressor is a frequent event in the development of tumors, and alterations or mutations in the gene are reported to occur in almost every type of cancer, at rates varying between 10% (in hematopoietic malignancies) and close to 100% (in high-grade serous carcinoma of the ovary).

In the case of keloids, an aberration in these pathways could influence the activity of TP53. But there are lingering questions that need to be explored, Dr. Garcia-Rodriguez said. “What was most important about this research was that the intermediate regulators and master regulators were found to be important in cell proliferation, senescence, apoptosis, and tumor suppression, suggesting a possible association, indirect or direct, with the development of keloids,” she said. “The big question that our group has was if TP53 is inactivated and there’s an aberrant process occurring with this drug, how come the keloid doesn’t actually turn into a cancer? And do these drugs and master regulators have the ability to influence these processes?”

In a nationwide survey, researchers from the Medical College of Wisconsin and the University of Pittsburgh Medical Center found that otolaryngology residents tend to rate their preparation for surgical cases as not particularly effective or efficient, with scores below four on a five-point scale for both junior and senior residents.

“The number of surgical education resources that are available seems to be increasing almost daily and, while we residents do have it easier now in the era of duty-hour restrictions, most would agree that residency is still very time-demanding,” said Jad Jabbour, MD, MPH, a fourth-year resident at the Medical College of Wisconsin in Milwaukee. “At the same time, we have evidence from other surgical fields that there’s often a disconnect between what staff surgeons or resident surgeons think is important to study before a case.”

The eight-question survey was distributed to every U.S. otolaryngology residency program and was completed by 108 residents. Junior residents rated their effectiveness in preparing for cases at 3.4 and their efficiency at 3.03, while senior residents, in their fourth and fifth years, rated those categories a 3.75 and 3.45, respectively. The differences between the resident groupings was significant for both questions (p=.008 for effectiveness and p=.02 for efficiency). Textbooks, surgical atlases, and surgical education websites were the most commonly cited resources used, with senior residents significantly more likely than junior residents to use journal articles (p=.01) and personal notes (p=.02).

For both groups, convenience was the most commonly cited reason for choosing a given resource, leading to the popularity of surgical websites, Dr. Jabbour noted, and lack of time the most commonly cited limitation in preparing for cases.

Junior residents were much more likely to report that the number of resources available is overwhelming. Asked to choose a single tool that would most improve their case preparation, residents chose, in almost equal numbers, a database of surgical videos, a resident-oriented website for graduated understanding, and a tool for finding “top-rated” resources.

“Case preparation is certainly not consistently rated as effective or efficient by residents right now, and while there does seem to be some progression through residency, there seems to be room for improvement in that at all levels,” Dr. Jabbour said. “There does seem to be some need for future resource development, but at the same we would like to improve the way we’re using the resources we already have.”

Thirty-Day Hospital Readmission Following Otolaryngology Surgery

An analysis of 30-day readmissions across more than 58,000 otolaryngology inpatient surgery discharges and a variety of hospital types has found that patient factors—and not hospital-level factors such as whether the surgery was performed at an academic center or not—are the main driving force behind whether or not a patient will be readmitted.

The analysis, from investigators at Washington University in St. Louis, Mo., used information from the State Inpatient Database, which is available through the U.S. Healthcare Cost and Utilization Project. In that database, patients are given a unique identifier, allowing them to be tracked over time, which overcomes a limitation of other literature—losing track of patients if they are readmitted at a center other than the original location of the surgery.

Researchers looked at the readmissions of California residents from 2008 to 2010. The data set included 58,748 discharges, approximately 500 of which were excluded because the original length of stay was more than 90 days or the surgery was done at a center with fewer than 10 otolaryngology admissions. The overall readmission rate was 8.1%, said Evan Graboyes, MD, a resident at the Washington University, who presented the findings.

Although univariate analysis showed that readmission rates were somewhat higher in teaching hospitals than non-teaching hospitals and in hospitals that serve a disproportionate share of low-income patients, those associations disappeared upon multivariate analysis, he said. “Variation in readmission rates between hospitals is driven by patient factors, not hospital factors,” Dr. Graboyes said.

Facial plastics and trauma (OR = 0.54) and endocrine procedures (OR = 0.77) were less likely to result in readmissions. Patients on Medicaid (OR = 1.27) or Medicare (OR = 1.54) were more likely to be readmitted, as were those with certain co-morbidities, including anemia, chronic lung disease, and renal failure. Surgical complications during the original hospital stay were not associated with a higher readmission risk on multivariate analysis, but medical complications during the original stay were (OR = 1.52). The highest risks for readmission were seen for patients discharged with home healthcare (OR = 2.23) or to a skilled nursing facility (OR = 2.21).

Dr. Graboyes said that figuring out how to lower readmission rates might be more of a challenge than assessing the risk factors. “In the readmission literature, this is often where things stop,” he said. “There are certain things that are not modifiable.” But while physicians and hospitals might not be able to alter factors such as co-morbidities and discharge to a nursing facility, they can change other factors associated with those risks, he said.

Hospitals, he recommended, can emphasize thorough prep and assessment of patients and their co-morbidities, so that procedures can be optimized for their needs. He also stressed coordination of post-discharge care, “whether that’s familiarizing them with otolaryngology wound care, instituting closer follow-up, triaging appropriate people, [or] making sure they have appropriate social support structure—all of those are important.”

Platelet-Rich Plasma and Platelet-Rich Fibrin in Otolaryngology

Researchers at the University of Toronto in Ontario, Canada, tried to determine why autologous platelet concentrates (APP) are not used more widely to promote healing after otolaryngology procedures, even though they have been found to be safe, they’re minimally invasive, and, in many settings, they’re not very expensive.

The products are concentrates of human platelets drawn from a patient’s blood in the operating room and re-injected locally, said Yael Bensoussan, MD, a resident at the University of Toronto who presented the findings. The principle is that concentrating platelets concentrates growth factors and adhesion molecules as well, causing a cascade of activity involved in the healing process.

The concentrates come in two forms: platelet-rich plasma (PRP), which requires two centrifugations to get the needed platelet concentration, and platelet-rich fibrin (PRF), which requires just one. Ready-to-use kits are available for $200 to $2,000, but if you already have a centrifuge, it costs very little, Dr. Bensoussan said. “Basically, if you have a centrifuge at your hospital setting, then the only costs are about $5 U.S. for the material to draw the blood and re-inject the product,” she said.

The researchers conducted anonymous surveys to assess the use of APP in otolaryngology compared with oral and maxillofacial surgery, where it is more commonly used. They surveyed members of the Canadian Society of Otolaryngology-Head and Neck Surgery (COHNS) and the Canadian Association of Oral and Maxillofacial Surgeons (COMFS) and found that 84% of COHNS respondents had heard of APP, and 14% were using it, while 99% of COMFS respondents had heard of it, and 30% were using it. The top reason given by members of COHNS for not using APP was a lack of knowledge about the product, followed by cost, a perceived lack of evidence in the literature, and lack of need. Among COMFS responders, a lack of evidence was the top reason given for not using APP, followed by cost and lack of need.

Indeed, researchers found, there are fewer than 30 articles in the otolaryngology literature on APP, compared with 400 published in the oral and maxillofacial literature.

In the literature that has examined its use, conclusions have been mixed in both fields. Dr. Bensoussan noted that results are hard to compare across studies because of the use of different products and methods. Plus, some of the procedures in which APP has been studied, including functional endoscopic sinus surgery and tonsillectomy, tend to heal well on their own already, making it difficult to show that APP improves healing. “Since we know that the products are safe [and] minimally invasive and that the cost can be minimal if you are in a hospital setting, we believe that otolaryngologists would benefit from learning about these products,” Dr. Bensoussan said.

Further study should include randomized controlled trials studying PRP and PRF separately and carefully analyzing the different methods used to apply or inject the product. She also suggested that research focus on “surgeries for which healing is problematic, such as tympanoplasty or wound healing in diabetic patients, in order to prove superiority of the products.”

Study results presented by Chen Lin, BA, a fourth-year medical student at The Ohio State University in Columbus, examined pain levels after tonsillectomy with coblation compared with electrocautery.

Coblation uses radiofrequency energy, which can ablate tissue at 40 to 70 degrees Celsius, compared with the 400 degrees necessary in electrocautery. Coblation also involves less heat reaching surrounding tissues, which means less thermal damage. The literature has yielded mixed results with respect to pain management, with some studies finding that coblation offers better pain control, while others do not show any significant difference between the methods.

The researchers looked prospectively at children aged 2 to 8 years who underwent tonsillectomy—66 with electrocautery and 117 with coblation. They found no significant difference at any of the time points, which included immediately after the procedure, then at five minutes, 15 minutes, 30 minutes and 60 minutes, but pain scores were lower at most time points, including 60 minutes later. Chen acknowledged that there might have been lingering anesthetic effects, and researchers are now planning to look at pain scores over a longer period. Pain after tonsillectomy is an important element to consider, Chen said. “Pain may play a role in delaying transfer of patients from the recovery unit to the floor or eventual discharge.”